DESCRIPTION (provided by principal investigator): It is estimated that 3.2 million African Americans aged 20 years or older have T2DM. This represents approximately 13 percent of the AA population and a significant proportion of the more than 20 million Americans believed to be living with diabetes, a disease that costs the U.S. over $174 billion a year in direct and indirect costs. Given current trends, 40-49 percent of AA born in 2000 will develop T2DM in their lifetime. Established diabetes risk factors such as diet and lifestyle play major roles in defining diabetes risk at a population level, but prediction of individual risk remains unrealized. Recent genome-wide association studies (GWAS) have successfully identified genetic variants that influence diabetes risk in European populations, however most do not have a major impact on diabetes risk in populations of African descent. The African American population from the Sea Islands of coastal South Carolina and Georgia has high rates of type 2 diabetes, low levels of admixture and, in general, consumes a diet rich in saturated fats. We postulate that this unique combination of ancestral and environmental factors results in a more consistent penetrance of diabetes risk alleles, as well as enrichment of risk alleles of African origin. The existing DNA samples and rich phenotypic data from the Sea Island Families Project comprise a unique resource for genetic studies of type 2 diabetes and related metabolic traits such as dyslipidemia. Our central hypothesis is that the increased risk for T2DM in AA compared with EA is due, in part, to susceptibility alleles of African origin, and that these alleles can be identified using a GWAS. The Specific Aims are to: 1) Identify genetic risk factors for type 2 diabetes utilizing DNA samples and data from the Sea Island Families Project (1,236 cases, 1,000 controls) and a GWAS approach;2) Conduct replication analyses of diabetes-associated genetic variants in independent African American populations using meta-analyses of GWAS data in collaboration with the Jackson Heart Study and Wake Forest University Study, and by genotyping up to 10,000 (1 percent) of the most-associated variants in subjects from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study, recruited from SC, GA and NC (1,000 cases, 1000 controls);3) Identify genetic contributors to lipoprotein subclasses in African Americans using the lipoprotein subclass profile (particle size and concentration for multiple subclasses of VLDL, LDL, and HDL) assessed by NMR at LipoScience, Inc., the GWAS data from Aim 1, and conduct replication by genotyping REGARDS subjects;4) Further explore replicated associations with follow-up studies in genes and regions of interest that may include (but are not limited to) bioinformatic evaluation of associated variants, increasing SNP density in associated regions, gene resequencing, and functional evaluation. The rationale for this project is that identification and validation of novel pathophysiological pathways and informed selection of candidate genes for diabetes risk will inform development of new, targeted prevention and treatment strategies in this underserved, high risk population. PUBLIC HEALTH RELEVANCE: Type 2 diabetes accounts for 90-95 percent of all diabetes and constitutes one of the most important public health problems in the U.S. and worldwide. Beyond the human cost, the direct and indirect costs of diabetes in the U.S. exceeded $1.7 billion in 2007. African American individuals are twice as likely to have type 2 diabetes as European Americans. Diabetes affects over 3.2 million African Americans, and leads to a devastating range of complications, including heart attack, stroke, kidney failure, blindness, amputation, and nerve pain. Given current trends, 40-49 percent of AA born in 2000 will develop T2DM in their lifetime. Established diabetes risk factors such as diet and lifestyle play major roles in defining diabetes risk at a population level, but prediction of individual risk remains unrealized. Identification of factors that place individuals at risk for type 2 diabetes is central to the development of therapeutic and preventive strategies. Recent genetic studies have successfully identified inherited factors that influence diabetes risk in European populations, however most do not have a major impact on diabetes risk in populations of African descent. The African American population from the Sea Islands of coastal South Carolina and Georgia has high rates of type 2 diabetes, and the existing Sea Island Families Project is a unique resource for identifying inherited factors for diabetes. We propose applying this proven strategy to identify new therapeutic targets and allow translation to novel diagnostic, prevention, and treatment strategies for type 2 diabetes.